Surgical site infections subjected to photodynamic therapy ... · Surgical site infections subjected to photodynamic therapy: a potential application in orthopaedic surgery. Hard

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Licensee OA Publishing London 2012. Creative Commons Attribution License (CC-BY)

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F�� : Jerjes W, Tan HB, Hopper C, Giannoudis PV. Surgical site infections subjected to photodynamic therapy: a potential application in orthopaedic surgery. Hard Tissue. 2012 Nov 10;1(1):9.

Surgical site infections subjected to photodynamic therapy: a potential application in orthopaedic surgery

W Jerjes1,2*, HB Tan1, C Hopper2, PV Giannoudis1

AbstractIntroductionPhotodynamic therapy, a minimally invasive oncological modality, has b-een in use for over 20 years. Howev-er, little clinical data is available on its non-oncological efficacy. Several laboratory-based trials on animals have suggested that this technology may be applicable as an antimicrobi-al therapy. In orthopaedics, where i-mplants and metal work are placed in deep tissue planes, a potential ris-k of infection is treated very serious-ly. Infection not only increases pat-ient morbidity and mortality but als-o the burden on healthcare system. Proposing a new modality that can instantly tackle this problem. This critical review discusses surgical site infections subjected to photodynam-ic therapy.ConclusionSurgical care should be state of the art with careful attention to strategi-es that avoid the development of SS-Is. When SSI does occur, superficial and deep wound infections can be treated using PDT by applying topic-al photosensitiser to the area follow-ed by light illumination.

IntroductionSurgical site infection (SSI) Nearly all surgical wounds are contaminated by microbes; however, in-nate immunity neutralises this effect. In few cases, infection may develop. SSIs account for 10% of all nosocomial infections. Although there is no international criterion

for diagnosis, authorities seem to agree that an infection of the tissues around or within the surgical wound within the first 4 weeks of surgery represents ‘surgical site infection’. SSI significantly increases patient morbidity as well as mortality1–6.

Incisional SSIs can be either superfi-cial (i.e. skin and subcutaneous tissue) or deep (i.e. fascial and muscle layers) or they can be organ/space SSIs; the latter may involve anatomical struc-tures that are either unopened or manipulated during the surgery1–6.

Several factors have been attributed to cause this surgical setback, including microbial- and host-related factors as well as surgical factors. Host-related factors involve age, medical back-ground, immunodeficiency, malnutri-tion, poor tissue perfusion and poor wound characteristics (such as poor skin, non-viable tissue, foreign body and haematoma). On the other hand, surgical factors include lengthy opera-tion, intraoperative contamination and poor surgical technique. Prolonged hospital stay, immobility and hypother-mia are responsible for majority of nosocomial infections, including SSIs1–6.

Simple SSIs usually present as a discharging skin wound, and some-times, a sinus can be identified track-ing to the skin surface from a deeper source. Involvement of deeper struc-tures may lead to abscess formation, thereby complicating management (i.e. pelvic and spinal infections)1–6.

Management is conventionally via antimicrobials and/or surgical approach. Surgical wound abscess is usually managed by incision, debridement and drainage. Deeper wounds are left open to allow healing from the inside out (i.e. healing by secondary inten-tion). Sometimes,

long-term antimicrobials are requir-ed, especially when dealing with inf-ections spreading tothe underlying structures (i.e. muscle and bone)1–6.

In orthopaedic surgery, SSIs are un-common; however, they can be devas-tating when theydo occur. Optimizing the patient’s general medical condi-tion pre-operatively and eliminating or diminishing the modifiable risk factors for infection has been shown to lower the risk of SSIs1–6.

Prophylactic antimicrobials and resistanceIn the 1960s, experimental data dem-onstrated the value of prophylactic antimicrobials. According to early studies at that time, high dose level of antibiotics in blood circulation has to be achieved at the time of first inci-sion in order to preventan infection. Prophylaxis is generally required for clean-contaminated and contaminated wounds. Most authorities recommend intravenous administration of pro-phylactic antimicrobials 30 min prior to the first incision7–13.

The use of prophylactic antimicro-bials in orthopaedic surgery prior to the first incision has shown to be effective in reducing SSIs, especially in open reduction and internal fixation in trauma surgery, spinal surgery as well as hip and knee surgeries7–13.

Staphylococcus aureus is most commonly identified in infected surgical wounds. Other bacteria such ascoagulase-negative staphylococci [including methicillin resistant Staph-ylococcus aureus (MRSA), which is proving to be a menace to modern day surgery], Escherichia coli, Pseudomonas aeruginosa

* Corresponding authorEmail: [email protected] Leeds Institute of Molecular Medicine, Leeds,

UK2 UCL Department of Surgery, London, UK

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and Enterobacter species have also been identified7–13. There has been an increase in the prevalence of antibiotic-resistant bacterial infectio-ns in clinical settings. This is mainly attributable to an increase in the prescription volume of anti-microbi-als, which in turn is attributable to various factors (Table 1). Antibiotic-resistance usually results from horizontal gene transfer as well as unlinked point mutations; four mec-hanisms have been identified: (1) drug inactivation or modification (i.e. some penicillin-resistant bact-eria), (2) alteration of metabolic pat-hways (i.e. sulphonamide-resistant bacteria), (3) alteration of target sites (i.e. MRSA and other pen-icillin-resistant bacteria), and (4) reduced drug accumulation. The most common of these pathogens are highlighted in Table 27–13.

It is only time before the emer-gence of new microbial strains that will be resistant to all known antimicrobial agents. The ability to manage deep surgical wounds via antibiotics may soon come to an end. The only remaining alternative may be surgery that could lead to tissue or limb loss, the latter being a significant loss to a patient. Despite attempts to modify and create new antimicrobials which may help tackle this problem, the problem may spersist as new mutant strains will eventually develop resistance to newly developed antimicrobial agents. This possibility was evident during the testing

phases of many new anti-microbial agents7–13. Another difficulty with developing new antimicrobials is safety, tolerability and toxicity of potential new drugs to humans. In the field of orthopaedic surgery, there is a need for a new modality that can overcome/sidestep the issue of multidrug resistance in bacterial strains, thereby reducing the burden on the patient and healthcare system.Photodynamic therapy (PDT)PDT represents a new modality that has been applied in clinical medicine and surgery for over two decades. This modality employs a photosensi-tiser that can either be introduced topically or systemically prior to tissue illumination with light. The resultant reaction between the light, photosensitiser and oxygen present in the tissues leads to a direct or programmed cell death and vascular shutdown14.

PDT has been successfully applied in the management of various tissue pathologies with promising results. Pathological tissues in the brain, head and neck, lungs, gastrointestinal tract and hepatobiliary organs, bladder, skin and even bone tumours have responded well to this modality14.

Very few reports have highlighted the effect of PDT as an antimicrobial modality in surgery. However, most of the published literature suggests that this modality may effectively eradicate infections, superficial or even deep seated ones, when effectively applied.

Several in vitro studies have identified PDT as an effective tool for inactivation of antibiotic-sensitive and antibiotic-resistant microorgan-isms. This could potentially benefit those patients who suffer from antibiotic-resistant infections or those who require prolonged antimicrobial therapy15,16.

The theory of photodynamic inacti-vation (PDI) necessitates cell exposure to specific wavelength light energy that leads to exogenous or endogenous exci-tation of photosensitiser molecules, resulting in the production of reactive oxygen species (ROS). ROS causes cell inactivation and death through modifi-cation of intracellular components. Advances in understanding of micro-bial pathophysiology have led to identi-fication of a series of pathways and phenotypes that serve as potentialtar-gets for antimicrobial drug discovery. Investigations of these phenotypic ele-ments in concert with PDT have been reported, which mainly focus on multi-drug efflux systems, biofilms, virulence and pathogenesis determinants. In many instances, the results are encour-aging; however, they are still at prelimi-nary phases and would require further investigations15,16.

PDT has been suggested as a new technique to inactivate microorgan-isms as it does not lead to the selec-tion of mutant resistant strains; a clear benefit in contrast to standard antibiotic therapy. This idea was ini-tially presented by Rabb (1900), who described the antimicrobial effect of acridine and light on Paramecium species. Soukos et al.17 studied the laser-induced effects of toluidine blue O on normal human gingival keratino-cytes and fibroblasts in vitro. The pre-liminary results of this study showed aneradication of Streptococcus san-guis, suggesting that a system for lethal photosensitisation of bacteria causing periodontal diseases could be developed. This demonstrated the microbial selectivity of PDT. PDI has

Table 1 Antibiotic-resistant bacterial infections

In appropriate prescribing: clinicians facing individuals who insist on anti bioti cs

In appropriate prescribing: clinicians simply prescribe as they feel they do not have ti me to explain why the anti bioti cs are not necessary

In appropriate prescribing: overly cauti ous clinicians for medico–legal reasons

Compliance with once-daily anti bioti cs is bett er than with twice-daily anti bioti cs

Prescribing subopti mum anti bioti c doses

Poor hand hygiene by hospital staff

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Table 2 Most common antibiotic-resistant pathogens

Bacterial species Description Frequent location

Illnesses caused Greatly-feared strains

Staphylococcus aureus

Facultati ve anaerobic, Gram-positi ve coccal bacterium

Normal skin and mucosal fl ora

Range from minor skin infecti ons to life-threatening diseases such as pneumonia, meningiti s, osteomyeliti s, endocarditi s, toxic shock syndrome, bacteraemia and sepsis

Methicillin-resistant Staphylococcus aureus

Streptococcus pyogenes

Spherical Gram-positi ve bacterium

Normal skin fl ora

Range from mild superfi cial skin infecti ons to life-threatening systemic diseases such as necroti zing fasciiti s, toxic shock syndrome, rheumati c fever and acute glomerulonephriti s

All produce virulence factors

Enterococcus Gram-positi ve cocci

Intesti nes Urinary tract infecti ons, bacteraemia, bacterial endocarditi s, diverti culiti s and meningiti s

Multi drug-resistant Enterococcus faecalis and Enterococcus faecium

Pseudomonas aeruginosa

Gram-negati ve, aerobic, rod-shaped bacterium

Normal skin fl ora and opportunisti c human pathogen

Infecti ons are generalized infl ammati on and sepsis, pneumonia, septi c shock, urinary tract infecti on, gastrointesti nal infecti on and skin and soft ti ssue infecti ons

Clostridium diffi cile

Anaerobic, spore-forming rods (bacilli)

Normal gut fl ora and opportunisti c gut pathogen

Severe diarrhoea and other intesti nal disease-associated diarrhoea and can lead to pseudomembranous coliti s

Escherichia coli

Gram-negati ve, rod-shaped bacterium

Normal lower intesti ne fl ora

Gastroenteriti s, urinary tract infecti ons, and neonatal meningiti s. In rarer cases, virulent strains are also responsible for haemolyti c-uremic syndrome, peritoniti s, masti ti s, septi caemia and Gram-negati ve pneumonia

Escherichia coli O157:H7

Salmonella Rod-shaped, Gram-negati ve

Zoonoti c facultati ve intracellular pathogens

Enteriti s, meningiti s, osteiti s and osteomyeliti s.

Horny/paratyphoid Salmonella

Acinetobacter baumannii

Aerobic Gram-negati ve bacterium

Opportunisti c infecti ons

Severe pneumonia and infecti ons of the urinary tract, bloodstream and other parts of the body

Mycobacterium tuberculosis

Aerobic and non-moti le bacteria

Mammalian respiratory system

Tuberculosis Hyper virulent strains of M. tuberculosis

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been studied in bacteria, where PDI of Escherichia coli was prim-arily dependent on genomic DNA photo damage18, while in other studies, cellular envelope appears to be the main component being assaulted by PDT19,20. In a study by Bertoloni et al., two S. aureus strains were subjected to PDT, and the electrophoretic analysis of cytoplasmic membrane proteins and DNA suggested that the mem-brane represented the primary target of the photo process, while the DNA may be a secondary target21.

Several studies have reported on the anti-staphylococcal activity of PDT. In vitro studies using various photosensitisers have shown a com-plete bactericidal effect on various bacteria, including MRSA22–30. Other Gram-positive bacteria have been investigated to a lesser extent; how-ever, they, including Propionibacterium acnes31,32 and Listeria monocytogenes33, have been reported to respond equally well to PDT.

The in vitro bactericidal effect of PDT on Gram-negative bacteria was also investigated and it was found to have a high bactericidal effect on Haemophilus parainfluenzae34, Prevotella and Por-phyromonas species35–37, Helicobacter mustelae38, E. coli B, Acinetobacter bau-mannii, and P. aeruginosa39,40. PDT of Gram-positive and Gram-negative bac-teria in animal models hasproven to be as successful as in in vitro studies in inactivating the causative bacteria41–46.

As yet, clinical PDT for infections has been mainly in the field of derma-tology using 5-aminolevulanic acid (5-ALA) and in dentistry using pheno-thiazinium dyes—a study concluded after peer-reviewing the published literature between 1960 and 2011. The authors expected to observe the applications of PDT to more challeng-ing infections using advanced antimi-crobial photosensitisers targeted to microbial cells in the years to come16. Except for E. coli, there was a significant decrease in the survival of

Staphylococcus intermedius, Strept-ococcus canis and P. aeruginosa fo-llowing ALA-PDT. A single treatme-nt required 2–3 h of light exposur-e. The data from this particular st-udy suggested that PDT may be a possible treatment option for wou-nd infections, but repeated treatm-ents or alterations in the photosen-sitiser or its carrier may be required to decrease treatment times41. The aim of this critical review is to discuss surgical site infections in orthopaedic surgery.

DiscussionApplication of PDT to surgical woundsThe literature reports significant advances in the application of PDT as an antimicrobial modality that targets those pathological microorganisms which cause wound infections. If this antimicrobial modality is applied properly using an appropriate photo-sensitiser and matching light proper-ties, a high bactericidal rate can be achieved. However, the efficacy and safety of PDT on surgical wounds re-quires confirmation by appropriately designed human clinical trials. With all this overwhelming evidence, there is no doubt that we are entering an age of human clinical trials when it comes to the inactivation of microor-ganisms using PDT16,41.

The issue of photosensitiser selec-tivity has been raised at a very early stage prior to clinical trials. Hamblin and Dai47 highlighted a crucial point with regard to selectivity—a photo-sensitiser that binds to microbial cells versus the one that binds to all other components in a complex milieu. According to these authors, theoreti-cally, 100 times more PDT is required to achieve the same high bactericidal effect that was achieved in in vitro and in vivo animal models. This was explained by an increase in the likeli-hood that the photosensitiser may bind to other components in a com-plex milieu, thereby reducing its availability for stronger PDT effect.

Furthermore, the photosensitiser and light penetration may be affecte-d by thick pus and dead tissue. It is expected that each wound should be opened and pus drained and that debridement and washout should be performed prior to the application of PDT in order to maximise the penetration of the photosensitiser and light. This would theoretically increase the efficacy of PDT. Challenges• Education to surgeons: an editorial

highlighted the fact that surgeonsdo not possess the adequate knowl-edge when it comes to PDT and itspotential applications47,48.

• Translation from laboratory scienceto human clinical trials: severalfactors need to be assessed andreviewed. These include elimina-tion of pathogens, selectivity, inflam-matory and immune processes ofhuman tissues, collateral damageand systemic effect47,48.

• PDT effect on the local vessels maycauseischaemia; this may poten-tially affect wound healing, leadingto re-infection47.

• Vascular and cellular mechanismsof the treated infective inflamma-tion may allow the involved tissueto defend and protect itself48.

• Long term effect of PDT exposureon human tissues.

• Continued local and systemic influ-ence of PDT once actual therapyhas ceased.

Proposing a trial A human clinical trial is a step in the right direction. We propose an open, phase I, dose-escalating and de-escalating study to evaluate the safety and efficacy of porphyrin- or ALA-based photosensitiser-based PDT in patients suffering from deep SSIs following trauma and orthopaedic operations. The primary objective of this study will be to assess the safety and efficacy of the porphyrin- or ALA-based photosensitiser and determine the maximal tolerated dose;

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Table 3 The design of the proposed human trial

Study design An open, phase I, dose-escalati ng and de-escalati ng study to evaluate the safety and effi cacy of porphyrin- or ALA-based photosensiti ser-based PDT in pati ents suff ering from deep SSIs post-trauma and orthopaedic operati ons. There will be a comparati ve arm.

Product Porphyrin-or ALA-based photosensiti ser

Centres University Teaching Hospital

Key dates Anti cipated start of pati ent recruitment: June 2012

Anti cipated end of pati ent recruitment: December 2013

Anti cipated end of pati ent follow-up: January 2014

Primary objecti ve To assess the safety and effi cacy of the porphyrin- or ALA-based photosensiti ser and determine the maximal tolerated dose

Secondary objecti ve To evaluate toxicity, including skin photosensiti vity

To determine the pharmacokineti cs of the drug in humans

To document the anti bacterial acti vity

Eligible pati ents Eligible pati ents will be included in 5 cohorts. The initi al interventi on will involve incision and drainage of the abscess, followed by the applicati on of the photosensiti ser. The initi al starti ng dose will be 2 mg/kg. The drug will be administered as a topical soluti on to washout the infected wound. The illuminati on will follow aft er 60 min. The illuminati on will be with red light (laser 630 nm), fl uence of 100–200 J/cm2 and fl uence rate of 10 mW/cm2. No anti bacterial cover will be administered aft er the interventi on.

Comparati ve arm Eligible pati ents will have incision, debridement and drainage of the deep surgical site abscess with anti bacterial cover as indicated in the local hospital microbiology guidelines.

Dose escalati on Will proceed according to a modifi cati on of Simon’s accelerated ti trati on design. The number of pati ents recruited will depend on the dose limiti ng toxicity (DLT) experienced. A total of 10 pati ents will be included at each dose level if no more than 1 pati ent experiences DLT.

Dose de-escalati on Additi onal cohorts may be added pending the outcome of the previous cohorts and discussions between the investi gators.

Disconti nuati on from the study

The disconti nuati on of a pati ent from the study will occur in an event of infecti on progression or DLT.

Target populati on Pati ents with SSIs requiring incision, debridement and drainage post-trauma and orthopaedic operati ons. SSIs to be subjected to PDT and verifi ed by microbiological investi gati ons include infecti ons caused by Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, non-life threatening Streptococcus pyogenes and Pseudomonas aeruginosa.

Safety An assessment of all adverse events experienced since treatment visit and assignment of CTCAE grades to all those considered to be drug related will be done at all visits. Adverse events will be followed unti l resolved. Blood sampling will be performed to check standard haematological and biochemical parameters and vital signs. Fluorescence and skin photosensiti vity will be measured and followed unti l values return to normal.

Study durati on Pati ent enrolment is esti mated to take 4 weeks. The study is expected to last for 19 months.

debridement and drainage post-trauma and orthopaedic operatio-ns. SSIs to be subjected to PDT and verified by microbiological investigations will include infecti-ons caused by S. aureus, MRSA, non-life threatening Streptococcus pyogenes and P. aeruginosa.

Patients will be enrolled for a period of 4 weeks and performance status will be recorded pre- and post- intervention. Each patient in the in-tervention and control groups will undergo incision and drainage. Topical photosensitiser will be administered

the secondary objective will be to evaluate the toxicity, including skin photosensitivity, in order to determine the pharmacokinetics of the drug in humans and to document the antibacte-rial activity (Table 3). The target population will include patients with SSIs requiring incision

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Table 4 Patient recruitment and follow-up in the proposed trial

VISIT NUMBER 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

VISIT DAY Day -1

Day 0

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

Day 9

Day 10

Day 11

Day 12

Day 13

Day 14

Day 21

Day 28

Pati ent demographics

√

Informed consenti ng

√

Inclusion/exclusion

√

Medical background

√ √ √ √ √

Current medicati ons

√ √ √ √ √

Pregnancy test √

Eye examinati on √ √ √ √ √

Stop anti bacterial Rx

√

Enrolment √

Bacterial strain √ √ √ √ √

Performance status

√ √ √ √ √ √

Booked for surgery

√

I&D performed √

Photosensiti ser administered

√

Illuminati on √

Pain scoring √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √

Vital signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √

Blood screening √ √ √ √ √ √ √ √ √ √ √ √ √

Blood and urine test PK

√ √ √ √ √ √ √ √ √ √ √

Microassessment √ √ √ √ √ √ √

Photography √ √ √ √ √ √ √ √ √ √ √ √ √

Fluorescence √ √ √ √ √ √ √ √ √ √ √ √ √

Skin sensiti vity testi ng

√ √ √ √ √ √ √ √ √ √ √ √

Bioluminescence √ √ √ √ √ √ √ √ √ √ √ √ √

Wound check √ √ √ √ √ √ √ √ √ √ √ √ √

Bactericidal eff ect √ √ √ √

Adverse events √ √ √ √ √

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at the site of the infected surgical wounds in the intervent-ion groups, and illumination will follow within 30 min. Pain scor-ing, vital signs, blood screening, blood and urine PK and microb-iological assessment will be perf-ormed on a regular basis. Asses-sment of the outcome will be do-cumented through clinical photogra-phy, fluorescence and skin sensitivity testing, bioluminescence, wound check and assessment of the bacteri-cidal effect. Adverse events will be documented and subsequently re-ported (Table 4).

ConclusionIn an ideal world, surgical care should be state of the art with careful attention to strategies that avoid the develop-ment of SSIs. As mentioned previously, optimisation of patient medical status (Table 5), appropriate aseptic tech-niques and surgical site preparation should help in preventing complica-tions. Intraoperatively, application of good basic surgical skills, accurate tis-sue dissection, suitable selection of suture materials and appropriate wound closure is paramount.

However, when SSI does occur, the wound should be immediately open-ed, pus evacuated and debridement and washout of the dead tissue and debris should be performed. During this time, antimicrobial

When resistance develops, a surge-on usually seeks input from a local microbiology department, which may suggest another medical ther-apy as guided by microscopy, cult-ure and sensitivity of the infected inflammatory sample acquired from the surgical wound. The new therapy is most likely to cover a wide spec-trum of pathogens, increasing the chance of developing multidrug-resistant strains. If the wound con-tinues to deteriorate, further surgical debridement may be indicated.

Superficial and deep wound infec-tions can be treated using PDT by applying topical photosensitiser to the area followed by light illumination. For example, in burn infections which carry high mortality, Gram-positive bacteria, especially S. aureus, colonize these wounds at an early stage and are known to develop multidrug-resistance. These can be inactivated by PDT in in vitro and in vivo animal models.

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Table 5 Optimisation of patient medical status

Maintaining close regulati on of blood sugar

Maintaining normal intraoperati ve core body temperature

Maintaining or increasing oxygen delivery to the wound by increasing the inspired oxygen concentrati on administered to the pati ent perioperati vely

Identi fying epidemics by common or uncommon microorganisms

Establishing the correct use of prophylaxis

Documenti ng costs, risk factors, and readmission rates

Monitoring post-discharge infecti ons and secondary consequences

Ensuring pati ent safety

Preventi ng emergence of resistance

cover is a requirement which will be guided by clinical wound healing and inflammatory markers.

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Surgical site infections subjected to photodynamic therapy ... · Surgical site infections subjected to photodynamic therapy: a potential application in orthopaedic surgery. Hard